Theoretical investigation of asymmetric C–H activation of cyclopropane

Abstract

Cyclopropanes are common structures in biochemical system. Herein, we studied the Pd(II)-catalyzed asymmetric C–H activation/arylation of chiral directing group-bound cyclopropane with computational methods. Mechanistic study with DFT calculation suggested that oxidative addition (OA) step is responsible for rate-determining. The analysis the transition state structures of this step revealed that the noncovalent interactions among the functional groups stabilize the major product TS to induce the stereselectivity. Analyzing by partitioning interacting moieties, the dispersion interaction was found to be main factor of interaction between the cyclopropylene (Cp) moiety and the side chain. Other factors including electrostatic interaction also plays role in the interaction between Cp and phenyl moiety. The model where the side chain of isoleucine amide auxiliary is replaced to perfluoro-tert-butyl could enhance these noncovalent interactions by C–H···F–C contact. Hammett analysis with respect of the substituents on phenyl and cyclopronylene was performed. This analysis indicates that the electron-withdrawing substituent of para-substituted iodobenzene gives decreased selectivity, because of the decrease of π-electron density of Ph weakens the $\pi$⋅⋅⋅H–C($sp^3$) interaction.